U.S. patent number 5,948,825 [Application Number 08/537,676] was granted by the patent office on 1999-09-07 for microemulsion preparation containing a slightly absorbable substance.
This patent grant is currently assigned to Institute for Advanced Skin Research Inc.. Invention is credited to Hiroshi Matsushita, Masao Takahashi.
United States Patent |
5,948,825 |
Takahashi , et al. |
September 7, 1999 |
Microemulsion preparation containing a slightly absorbable
substance
Abstract
Microemulsion preparation in which a plurality of specified
surfactants are combined such that aqueous-phase droplets that
contain a physiologically active substance of low absorption and
which have an average size of 0.4-100 nm are dispersed in an
oil-phase dispersion medium. In order to improve its low
transdermic or transmucosal absorbability, the physiologically
active substance is allowed to be present as dissolved in the
aqueous-phase droplets in the W/O emulsion. The preparation is low
in local irritation and uses neither malodorous substances such as
higher alcohols nor conventional absorption enhancers.
Inventors: |
Takahashi; Masao (Tokyo,
JP), Matsushita; Hiroshi (Tokyo, JP) |
Assignee: |
Institute for Advanced Skin
Research Inc. (Kanagawa-ken, JP)
|
Family
ID: |
14026380 |
Appl.
No.: |
08/537,676 |
Filed: |
October 19, 1995 |
PCT
Filed: |
April 19, 1994 |
PCT No.: |
PCT/JP94/00645 |
371
Date: |
October 19, 1995 |
102(e)
Date: |
October 19, 1995 |
PCT
Pub. No.: |
WO94/23749 |
PCT
Pub. Date: |
October 27, 1994 |
Foreign Application Priority Data
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|
|
Apr 19, 1993 [JP] |
|
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5-91438 |
|
Current U.S.
Class: |
424/85.2;
514/807; 514/808; 514/10.9; 514/5.9; 514/7.7; 514/9.7;
514/11.9 |
Current CPC
Class: |
A61K
9/1075 (20130101); Y10S 514/807 (20130101); Y10S
514/808 (20130101) |
Current International
Class: |
A61K
9/107 (20060101); A61K 009/107 () |
Field of
Search: |
;424/434,85.1,85.2,85.4,85.5,85.6,85.7 ;514/807,808,937
;530/303,307,315,380
;930/60,90,140,145,150,DIG.560,DIG.660,DIG.670 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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135171-A2 |
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Mar 1985 |
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EP |
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0152945 |
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Aug 1985 |
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EP |
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366277-A2 |
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May 1990 |
|
EP |
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0610502 |
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Sep 1992 |
|
EP |
|
9218147 |
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Oct 1992 |
|
WO |
|
9302664 |
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Feb 1993 |
|
WO |
|
9302665 |
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Feb 1993 |
|
WO |
|
9305805 |
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Apr 1993 |
|
WO |
|
9408605 |
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Apr 1994 |
|
WO |
|
9408603 |
|
Apr 1994 |
|
WO |
|
9419001 |
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Sep 1994 |
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WO |
|
Primary Examiner: Harrison; Robert H.
Attorney, Agent or Firm: Browdy and Neimark
Claims
We claim:
1. A water-in-oil microemulsion preparation containing a slightly
absorbable physiologically active substance in an aqueous phase
comprising a trialiphatic C.sub.8 -C.sub.10 glyceryl ester, said
microemulsion consisting essentially of an oil phase, an aqueous
phase and a combination of surfactants, said oil phase comprising
trialiphatic C.sub.8 -C.sub.10 glyceryl ester as the dispersion
medium said combination of surfactants consisting essentially of at
least one surfactant in class (c) in combination with at least one
surfactant in class (a) or class (b), wherein said classes of
surfactants are:
(a) an ionic surfactant selected from the group consisting of
di-2-ethylhexylsulfosuccinic acid sodium and sodium
dodecylsulfate;
(b) a nonionic surfactant with an HLB of 10-20 selected from the
group consisting of a polyoxyethylene-added hardened castor oil
containing an average of 40 to 60 moles of oxyethylene in the
polyoxyethylene moiety, sodium monooleate polyoxyethylene wherein
the polyoxyethylene moiety contains an average of 10-40 moles of
ethylene glycol, and a polyoxyethylene lauryl ether, wherein the
polyoxyethylene moiety has 4 to 25 moles of oxyethylene; and
(c) a nonionic surfactant with an HLB of from 3 to 7 selected from
the group consisting of, monooleic acid diglyceryl ester, sorbitan
sesquioleate and a polyoxyethylene-added hardened castor oil having
an average of from 8 to 12 moles of oxyethylene in the
polyoxyethylene moiety;
wherein the particle size of the particles in the microemulsion is
0.4-100 nanometers as determined by a laser light scattering
particle size analyzer.
2. A microemulsion preparation according to claim 1 wherein the
slightly absorbable physiologically active substance is selected
from the group consisting of vasopressin, calcitonin,
erythropoietin, colony-stimulating factor, interleukins,
interferons, insulin, and accessory thyroid hormone.
3. A microemulsion preparation according to claim 1 wherein the
slightly absorbable physiologically active substance is selected
from the group consisting of vasopressin, calcitonin,
erythropoietin, colony-stimulating factor, interleukins,
interferons, insulin, and accessory thyroid hormone.
4. A microemulsion preparation according to claim 2 wherein the
slightly absorbable physiologically active substance is selected
from the group consisting of vasopressin, calcitonin,
erythropoietin, colony-stimulating factor, interleukins,
interferons, insulin, and accessory thyroid hormone.
5. A microemulsion preparation according to claim 1 which is
formulated in a dosage form suitable for transdermic, peroral or
transmucosal administration.
Description
TECHNICAL FIELD
This invention relates to a microemulsion preparation that contains
a physiologically active substance such as a high-molecular weight
peptide which inherently can not be easily absorbed through the
skin or mucous membrance but which is incorporated in such a way
that its absorption through the skin or mucous membrance is
improved.
BACKGROUND ART
The preparation of microemulsions is one attempt that has been made
to improve the absorption of physiologically active substances
through the skin or mucous membrane.
Microemulsions have been proposed that use alcohols such as octanol
and butanol. However, they are not particularly suitable for oral
administration since the alcohols they use have malodors. If
microemulsions are prepared using large amounts of ionic
surfactants, they are irritant to the mucous membrane and skin.
Peptides such as insulin and calcitonin have low absorbability
through the mucous membrane. With a view to dealing with this
problem, the use of absorption enhancers such as bile salts has
been attempted but they have been found to damage or destroy
epithelial cells of the mucous membrane.
DISCLOSURE OF INVENTION
An object of the invention is to prepare a microemulsion that is
less irritating to the mucous membrane and skin and which uses
neither malodorous higher alcohols such as butanol and octanol nor
conventional absorption enhancers such as bile salts that will
damage epithelial cells. It is another object of the invention to
improve the absorption of certain physiologically active substances
through the skin or mucous membranes by means of preparing such
microemulsions.
The invention provides a microemulsion preparation that
successfully solves the aforementioned problems of the prior art by
combining at least two specified surfactants.
The surfactants to be used in the invention are selected from the
following three classes (a), (b) and (c), among which a surfactant
in class (c) is essential and combined with a surfactant in either
one of classes (a) and (b). The surfactants in the respective
classes are as follows:
(a) an ionic surfactant:
di-2-ethylhexylsulfosuccinic acid sodium; and
sodium alkylsulfate (the alkyl moiety has 8-20, preferably 10-14,
carbon atoms);
(b) a nonionic surfactant with an HLB of 10-20:
a polyoxyethylene hardened or unhardened castor oil (oxyethylene is
added in 30-80, preferably 40-60, moles on average);
an ester of polyethylene glycol and higher aliphatic acid (the
aliphatic acid is a saturated or unsaturated aliphatic acid having
16-20, preferably 18, carbon atoms and ethylene glycol is added in
10-40 moles on average); and
a polyoxyethylene alkyl ether (the alkyl moiety has 8-14,
preferably 12, carbon atoms and oxyethylene is added in 4-25 moles
on average); and
(c) a nonionic surfactant with an HLB of 3-7:
a mono- or polyglycerin aliphatic acid ester (the aliphatic acid is
a saturated or unsaturated aliphatic acid having 16-20, preferably
18, carbon atoms and it is added in 1-2 moles per mole of glycerin,
which is added in 0-4 moles);
a sorbitan aliphatic acid ester (the aliphatic acid is a saturated
or unsaturated aliphatic acid having 16-20, preferably 16-18,
carbon atoms and added in 1-3 moles); and
a polyoxyethylene hardened or unhardened castor oil (oxyethylene is
added in 3-20, preferably 8-12, more preferably 10, moles on
average).
The dispersion media that can be used in the invention are fats or
oils that are not irritating to the skin or mucous membranes and
which are liquid at room temperature or dissolve when heated by the
body temperature to become liquid. Specific examples that may be
used include edible vegetable or animal oils (aliphatic acid
glycerin esters) such as soybean oil, sesame oil and olive oil;
saturated or unsaturated aliphatic acids; and mono-, di- or
triglycerin esters of middle-chain aliphatic acids (C.sub.6
-C.sub.18).
The microemulsion of the invention can be prepared by a
conventionally known method as follows.
A suitable combination of surfactants is added to an oil component
as a dispersion medium and the ingredients are agitated and mixed
thoroughly to prepare a uniform oily mixture. When the oil
component is solid at room temperature, it is heated to melt the
oil component before the surfactants are added and mixed. An active
ingredient, or a physiologically active substance, such as
calcitonin, erythropoietin or other peptide is dissolved in
water.
The thus prepared aqueous solution of the physiologically active
substance is added to the separately prepared oily mixture under
agitation. Further agitation yields a microemulsion as a clear
liquid. If necessary, an additional amount of the oil component may
be added to adjust the concentration of the active ingredient.
The microemulsion thus obtained has dispersed droplets in sizes of
0.4-100 nm, preferably 1-100 nm, and hence is very stable.
If desired, albumin, glycerin, glycol and any other stabilizers may
be incorporated in the aqueous phase.
The physiologically active substances of low absorbability through
the skin or mucous membrane that can be applied in the invention
include peptide drugs such as vasopressin, calcitonin,
erythropoietin, colony stimulating factor, interleukins,
interferons, insulin and accessory thyroid hormone, as well as
slightly absorbable low-molecular weight (.ltoreq.1,000) drugs.
Such low-molecular weight drugs are exemplified by the
following:
(1) antibiotics: aclarubicin HCl, oxytetracrycline HCl, cefotiam
HCl, carbenicillin sodium, cefmetazole sodium, etc.;
(2) antiarrythmics: procainamide HCl, disopyramide phosphate,
lidocaine HCl, etc.:
(3) cardiotonics: etilefrine HCl, dopamine HCl, etc.;
(4) vasodilators: trapidil, etc.:
(5) local anesthetics: oxybuprocaine HCl, dibucaine HCl, procaine
HCl, etc.;
(6) antitumors: bleomycin HCl, cytarabine, procarbazine HCl,
cisplatin, vinblastine HCl, neocarzinostatin, doxorubicin HCl,
etc.;
(7) agents acting on the autonomic nerve system: distigmine
bromide, bethanechol chloride, propantheline bromide, etc.;
(8) antipyretic, analgesic antiinflammatories: antipyrine,
tiaramide HCl, diclofenac sodium, etc.;
(9) agents acting on psychic nerves: imipramide HCl, clomipramine
HCl, tiodaline HCl, flurazepam HCl, chlorpromazine HCl,
levomepromazine HCl, etc.;
(10) narcotic analgesic/antitussive agents: oxycodone HCl,
etc.;
(11) antispasmodics: cyclopentolate, etc.;
(12) antiparkinsonian drugs: amantadine HCl, promethazine HCl,
metixene HCl, etc.;
(13) other agents acting on circulatory organs: diltiazem HCl,
trimetazidine HCl, etc.;
(14) hypotensives: dihydroergotoxin mesilate, clonidine HCl,
etc.;
(15) enzyme preparations: urokinase, hyaluronidase, etc.;
(16) others: naphazoline HCl, meclofenoxate HCl, methylephedrine
HCl, homatropine hydrobromide, etc.
The relative proportions of the ingredients in the microemulsion of
the invention are indicated below in terms of the ratio of water to
each ingredient on a volume basis.
The ratio of water to surfactant ranges from 1:2 to 1:200,
preferably from 1:3 to 1:20.
The ratio of water to oil component ranges from 1:3 to 1:5,000,
preferably from 1:6 to 1:5,000.
The drug-containing microemulsion thus prepared is formulated in
various dosage forms for absorption through either the skin or
mucous membranes or peroral administration and common
pharmaceutical formulation procedures may be employed as described
below.
For absorption through the mucous membranes:
a) nasal drug: a spray container for nasal application is filled
with the microemulsion, which is to be sprayed over the nasal
mucosa;
b) rectal suppository: a suitable heat-fusible material such as
polyethylene glycol which is not soluble in oils is heated to melt
and fed into a mold to form a hollow shell, which is filled with
the microemulsion. The opening in the shell is closed with a melt
of the same heat-fusible material, whereby the microemulsion is
confined in the closed shell. The thus prepared suppository is
inserted into the rectum for actual use.
Alternatively, an oleaginous base that melts within the rectum is
used as an oil component and while it is molten, water is added and
the ingredients are mixed under agitation to form a microemulsion,
which is cooled to solidify to a suppository form. The thus
prepared suppository is inserted into the rectum for actual
use.
For peroral administration:
The body of a hard gelatic capsule is filled with the microemulsion
and slipped on a cap, with a gelatin solution being applied to the
junction to form a barrier against leakage of the drug. After
drying, the capsule is coated with an enteric substance such as
hydroxypropylmethyl cellulose phthalate (HPMC) to formulate an
enteric preparation, which is subsequently dried and administered
perorally as required.
The hard gelatin capsule may be replaced by a soft gelatin
capsule.
The following examples and experimental data are provided for the
purpose of further illustrating the invention.
EXAMPLE 1
______________________________________ Di-2-ethylhexylsulfosuccinic
acid sodium 7 g (surfactant 1) Monooleic acid diglyceryl ester (HLB
= 5.5) 5 g (surfactant 2) Isotonic phosphate buffer solution 2 g
(aqueous component) Calcitonin (drug) 5 mg Trialiphatic acid
(C.sub.8 -C.sub.10) glyceryl ester to make 100 g (oil component)
______________________________________
To about 90% of the oil component, surfactant 1 [in class (a)] and
surfactant 2 [in class (b)] were added and stirred thoroughly. In a
separate step, calcitonin was dissolved in the aqueous component.
The aqueous solution of calcitonin was added to the stirred mixture
of the oil component and the surfactants. Further stirring gave a
clear liquid. Under continued stirring, the remainder of the oil
component was added to make a total volume of 100 g.
The thus prepared liquid was subjected to measurement with a laser
light scattering particle size analyzer (Model DLS700 of Ohtsuka
Denshi K.K.; Ar laser; maximum output, 15 mW) and it was found to
be a W/O microemulsion having an average particle size of 14
nm.
EXAMPLE 2
______________________________________ Polyoxyethylene hardened
castor oil 8 g (EO = 40; HLB = 12.5) (surfactant 1) Monooleic acid
diglyceryl ester (HLB = 5.5) 8 g (surfactant 2) Isotonic phosphate
buffer solution containing 1 g bovin serum albumin (aqueous
component) Erythropoietin (drug) 1.25 mg Trialiphatic acid (C.sub.8
-C.sub.10) glyceryl ester to make 100 g (oil component)
______________________________________
To about 90% of the oil component, surfactant 1 [in class (b)] and
surfactant 2 [in class (c)] were added and stirred thoroughly.
Surfactant 1, which was semi-solid at room temperature, was heated
during the agitation. In a separate step, erythropoietin was
dissolved in the aqueous component. The mixture of the oil
component and the surfactants was cooled to room temperature and
the aqueous solution of erythropoietin was added to the stirred
mixture. Further stirring gave a clear liquid. Under continued
stirring, the remainder of the oil component was added to make a
total volume of 100 g.
The thus prepared liquid was subjected to measurement with a laser
light scattering particle size analyzer (Model 370 of NICOMP Inc.;
Ar laser; maximum output, 70 mW) and it was found to be a W/0
microemulsion having an average particle size of 30 nm.
EXAMPLE 3
______________________________________ Polyoxyethylene (20 moles)
hardened castor oil 4 g (HLB = 10.5) (surfactant 1) Polyoxyethylene
(10 moles) hardened castor oil 10 g (HLB = 6.5) (surfactant 2)
Isotonic phosphate buffer solution 1 g (aqueous component)
Alpha-interferon (drug) 500 .mu.g Soybean oil (oil component) to
make 100 g ______________________________________
To about 90% of the oil component, surfactant 1 [in class (b)] and
surfactant 2 [in class (c)] were added and stirred thoroughly. In a
separate step, the interferon was dissolved in the aqueous
component. The aqueous solution of interferon was added to the
stirred mixture of the oil component and the surfactants. Further,
stirring gave a clear liquid. Under continued stirring, the
remainder of the oil component was added to make a total volume of
100 g.
The thus prepared liquid was subjected to measurement with a laser
light scattering particle size analyzer (Model 370 of NICOMP Inc.,
see supra) and it was found to be a W/O microemulsion having an
average particle size of 30 nm.
EXAMPLE 4
______________________________________ Calcitonin (drug) 2.0 mg
Isotonic phosphate buffer solution 1 ml (aqueous component)
Sorbitan monooleate POE (20) (HLB = 15.0) 2.0 g (surfactant 1)
Monooleic acid diglyceryl ester (HLB = 5.5) 10.0 g (surfactant 2)
Middle-chain aliphatic acid triglyceride (oil component) 100 ml in
total ______________________________________
Calcitonin was dissolved in the aqueous component. Surfactant 1 [in
class (b)] and surfactant 2 [in class (c)] were added to 80% of the
oil component and the ingredients were stirred to form a solution.
The calcitonin solution was added to the oil component having the
surfactants dissolved therein and the mixture was stirred.
Continued stirring gave a clear microemulsion, to which the
remainder of the oil component was added to make a total volume of
100 ml. The resulting liquid was subjected to measurement with a
laser light scattering particle size analyzer (Model DLS-7000 of
Ohtsuka Denshi K.K.; Ar laser; maximum output, 75 mW) and it was
found to be a very fine microemulsion having an average particle
size of 2.4 nm.
A mixture of this microemulsion with water was subjected to ultra
centrifugation and the content of calcitonin in the resulting
aqueous phase was determined; 92% of the calcitonin added to make
the microemulsion could be recovered (when 1 g of calcitonin was
added, a total of 0.92 g could be recovered).
EXAMPLE 5
______________________________________ G-CSF (drug) 500 .mu.g
Isotonic phosphate buffer solution 1 ml (aqueous component)
Di-2-ethylhexylsulfosuccinic acid sodium 7.0 g (surfactant 1)
Monooleic acid diglyceryl ester (HLB = 5.5) 5.0 g (surfactant 2)
Middle-chain aliphatic acid triglyceride 100 ml (oil component)
______________________________________
G-CSF was dissolved in the aqueous component. Surfactant 1 [in
class (a)] and surfactant 2 [in class (c)] were added to 80% of the
oil component and the ingredients were stirred to form a solution.
The G-CSF solution was added to the oil component having the
surfactants dissolved therein and the mixture was stirred.
Continued stirring gave a clear microemulsion, to which the
remainder of the oil component was added to make a total volume of
100 ml. The resulting liquid was subjected to measurement with a
laser light scattering particle size analyzer (Model DLS-7000 of
Ohtsuka Denshi K.K., see supra) and it was found to be a very fine
microemulsion having an average particle size of 6.5 nm.
A mixture of this microemulsion with water was subjected to ultra
centrifugation and the content of G-CSF in the resulting aqueous
phase was determined; 89% of the G-CSF added to make the
microemulsion could be recovered.
EXAMPLE 6
______________________________________ G-CSF (drug) 500 .mu.g
Isotonic phosphate buffer solution 1 ml (aqueous component)
Polyoxyethylene (9) lauryl ether (HLB = 14.5) 10.0 g (surfactant 1)
Sorbitan sesquioleate (HLB = 3.7) 2.0 g (surfactant 2) Middle-chain
aliphatic acid triglyceride (oil component) 100 ml in total
______________________________________
G-CSF was dissolved in the aqueous component. Surfactant 1 [in
class (b)] and surfactant 2 [in class (c)] were added to 80% of the
oil component and the ingredients were stirred to form a solution.
The G-CSF solution was added to the oil component having the
surfactants dissolved therein and the mixture was stirred.
Continued stirring gave a clear microemulsion, to which the
remainder of the oil component was added to make a total volume of
100 ml. The resulting liquid was subjected to measurement with a
laser light scattering particle size analyzer (Model DLS-7000 of
Ohtsuka Denshi K.K., see supra) and it was found to be a
microemulsion having an average particle size of 44 nm.
A mixture of this microemulsion with water was subjected to ultra
centrifugation and the content of G-CSF in the resulting aqueous
phase was determined; 86% of the G-CSF added to make the
microemulsion could be recovered.
EXAMPLE 7
______________________________________ Carbenicillin sodium (drug)
400 mg Distilled water (aqueous component) 1.0 ml Sorbitan
monooleate polyoxyethylene (20) 2.0 g (HLB = 15.0) (surfactant 1)
Sorbitan sesquioleate (HLB = 3.7) 10.0 g (surfactant 2)
Middle-chain aliphatic acid triglyceride (oil component) 100 ml in
total ______________________________________
Carbenicillin was dissolved in the aqueous component. Surfactant 1
[in class (b)] and surfactant 2 [in class (c)] were added to 80% of
the oil component and the ingredients were stirred to form a
solution. The carbenicillin solution was added to the oil component
having the surfactants dissolved therein and the mixture was
stirred. Continued stirring gave a clear microemulsion, to which
the remainder of the oil component to make a total volume of 100
ml. The resulting liquid was subjected to measurement with a laser
light scattering particle size analyzer (Model DLS-7000 of Ohtsuka
Denshi K.K., see supra) and it was found to be a microemulsion
having an average particle size of 9.2 nm.
EXAMPLE 8
______________________________________ Antipyrine (drug) 200 mg
Distilled water (water component) 1 ml Di-2-ethylhexylsulfosuccinic
acid sodium 7.0 g (surfactant 1) Monooleic acid diglyceryl ester
(HLB = 5.5) 5.0 g (surfactant 2) Middle-chain aliphatic acid
triglyceride (oil component) 100 ml in total
______________________________________
Antipyrine was dissolved in the aqueous component. Surfactant 1 [in
class (a)] and surfactant 2 [in class (c)] were added to 80% of the
oil component and the ingredients were stirred to form a solution.
The antipyrine solution was added to the oil component having the
surfactants dissolved therein and the mixture was stirred.
Continued stirring gave a clear microemulsion, to which the
remainder of the oil component was added to make a total volume of
100 ml.
EXAMPLE 9
______________________________________ Propantheline bromide (drug)
100 mg Distilled water (aqueous component) 1 ml
Di-2-ethylhexylsulfosuccinic acid sodium 7.0 g (surfactant 1)
Monooleic acid diglyceride (HLB = 5.5) 5.0 g (surfactant 2)
Middle-chain aliphatic acid triglyceride (oil component) 100 ml in
total ______________________________________
Propantheline bromide was dissolved in the aqueous component.
Surfactant 1 [in class (a)] and surfactant 2 [in class (c)] were
added to 80% of the oil component and the ingredients were stirred
to form a solution. The propantheline bromide solution was added to
the oil component having the surfactants dissolved therein and the
mixture was stirred. Continued stirring gave a clear microemulsion,
to which the remainder of the oil component was added to make a
total volume of 100 ml.
EXAMPLE 10
______________________________________ Procainamide HCl (drug) 400
mg Distilled water (aqueous component) 1.0 ml Polyoxyethylene (9)
lauryl ether (HLB = 14.5) 10.0 g (surfactant 1) Sorbitan
sesquioleate (HLB = 3.7) 2.0 g (surfactant 2) Middle-chain
aliphatic acid triglyceride (oil component) 100 ml in total
______________________________________
Procainamide HCl was dissolved in the aqueous component. Surfactant
1 [in class (b)] and surfactant 2 [in class (c)] were added to 80%
of the oil component and the ingredients were stirred to form a
solution. The procainamide HCl solution was added to the oil
component having the surfactants dissolved therein and the mixture
was stirred. Continued stirring gave a clear microemulsion, to
which the middle-chain aliphatic acid triglyceride was added to
make a total volume of 100 ml.
EXAMPLE 11
______________________________________ Riboflavin phosphate sodium
(drug) 10 mg Distilled water (aqueous component) 1 ml
Di-2-ethylhexylsulfosuccinic acid sodium 7.0 g (surfactant 1)
Monooleic acid diglyceryl ester (HLB = 5.5) 5.0 g (surfactant 2)
Middle-chain aliphatic acid triglyceride (oil component) 100 ml in
total ______________________________________
Riboflavin phosphate sodium was added to the aqueous component and
the ingredients were stirred to form a solution. Surfactant 1 [in
class (a)] and surfactant 2 [in class (c)] were added to the oil
component and the ingredients were stirred to form a solution, to
which the riboflavin phosphate sodium solution was added and the
mixture was stirred. Continued stirring gave a clear, pale yellow
microemulsion.
EXAMPLE 12
______________________________________ Amaranth (model compound) 1
mg Distilled water (aqueous component) 1 ml Sodium dodecylsulfate
(surfactant 1) 4.0 g Monooleic acid diglyceryl ester (HLB = 5.5)
6.0 g (surfactant 2) Middle-chain aliphatic acid triglyceride (oil
component) 100 ml in total
______________________________________
A red pigment Amaranth* was dissolved as a model compound (drug
substitute) in water. Surfactants 1 and 2 were added to 80% of the
oil component and the mixture was stirred for 60 min to prepare a
dispersion of the surfactants. The aqueous component having
Amaranth dissolved therein was added to the oil component having
the surfactants dispersed therein and the mixture was stirred for
80 min. Upon standing, a supernatant formed and it was collected
and centrifuged at 7000 rpm for 40 min to give a clear liquid. This
liquid was subjected to measurement with a laser light scattering
particle size analyzer (Model DLS-7000 of Ohtsuka Denshi K.K., see
supra) and it was found to have an average particle size of 52 nm.
The volume of this liquid was doubled by addition of water and upon
super-high-speed centrifugation at 5000 rpm for 1.5 h, a slightly
red aqueous phase formed.
* Amaranth:
3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic
acid trisodium salt
Experiment on the Absorbability of Drug-Containing Emulsions
(Methods)
(1) Absorption through the skin:
A piece of lint (3.times.4 cm) lined with a polyethylene sheet
(4.times.5 cm) was coated uniformly with 0.4-0.7 ml of the
drug-containing microemulsion prepared in Example 1 or 2. Rats were
shaven on the back, to which the lint and a stretchable bandage
were applied in that order. Blood was sampled from the rats at
specified time intervals and the concentration of the drug in the
blood was determined.
(2) Absorption by the alimentary tract:
Rats were incised in the abdomen and a silicone rubber tube was
passed through the alimentary tract from the stomach wall to the
duodenum, followed by suturing of the stomach wall, peritoneum and
skin through which the tube penetrated. After the rats recovered
from the operative invasion, the drug-containing microemulsion
prepared in Example 1 or 2 was administered via the silicone rubber
tube, which was then closed. As in (1), blood was sampled at
specified time intervals and the concentration of the drug in the
blood was determined.
(3) Absorption by the rectum (through the mucous membrane):
Rats were starved from the day before experiment until there was
little feces left in the abdomen. Then, a rubber band was applied
to the anus of each animal, through which a tube was inserted for
injecting a predetermined amount of the drug-containing
microemulsion prepared in Example 1 or 2. Immediately after the
injection, the anus was bound with a rubber band to prevent the
leakage of the microemulsion. Blood was sampled at specified time
intervals and the concentration of the drug in the blood was
determined.
(4) Administration into the nasal cavity:
Administration into the nasal cavity was performed by a closure
technique in accordance with the method of Hirai et al.
(INTERNATIONAL JOURNAL OF PHARMACEUTICS, 7 (1981) 317-325). Rats
were anesthetized and medisected in the neck to expose the windpipe
and esophagus. Part of the windpipe was incised and a polyethylene
tube was inserted into the windpipe to secure the airway, followed
by ligation. The nostril and the opening in the incisive caval on
the oral cavity side were closed with an adhesive. Part of the
esophagus was incised for insertion of a nutrition catheter until
its end reached into the nasal cavity. The part of the esophagus
into which the nutrition catheter was inserted was ligated. The
drug-containing microemulsion prepared in Example 1 or 2 was
injected into the animals via the nutrition catheter. Blood was
sampled at specified time intervals and the change in the
concentration of the drug in the blood was determined over
time.
(Results)
The data on the absorption of the microemulsions prepared in
accordance with the invention are shown in Table 1 for three
different routes, transdermic, peroral (by the alimentary tract)
and permucosal (or by the rectum).
None of the microemulsions tested caused local irritation in any
regions including the skin and mucous membranes.
TABLE 1 ______________________________________ Availability*
Microemulsion Site of administration Surfac- Duode- Nasal Peptide
tant Example num Skin Rectum cavity
______________________________________ EPO a + c 1(*1) 2.6% 1.2%
1.7% -- b + c 2 1.1% -- -- -- Calci- a + c 1 2.3% 3.5% 22.5% 50%
tonin ______________________________________ Availability: Relative
value with the availability upon subcutaneous injection (i.e.,
integrated blood concentration over time) being taken as 100%.
(*1)According to Example 1, except that calcitonin was replaced by
erythropoietin.
(Evaluation of the Experimental Data)
For macromolecular peptides such as erythropoietin, availability
values of 2-3% are remarkable. Speaking of calcitonin, the
availability 22-23% due to rectal absorption and the value 50% due
to absorption by the nasal cavity are both satisfactory for
practical purposes.
* * * * *